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The Diagnosis and Treatment of Sterility Due to Ovarian Dysfunction: An Analysis of 43 Cases
The Diagnosis and Treatment of Sterility Due to Ovarian Dysfunction An Analysis of 43 Cases
Inglis F. Frost, M.D.
to ovarian dysfunction is one of the most difficult sterility problems the physician is called upon to treat. It constitutes about one-fifth of all the conditions which contribute to the infertility of the married couple. There are many factors which may cause sterility aside from ovarian dysfunction and any one of these, or more than one, may accompany the nonfunctioning ovary. These must be eliminated before deciding that the sterility is due only to a hormonal deficiency. Many endocrinologists feel that the treatment of sterility due to ovarian dysfunction is without merit. This is undoubtedly true of certain cases in which the dysfunction is so fundamental that any type of hormonal treatment to re-establish ovulation would be a useless procedure. There are many cases, however, in which the ovarian deficiency can be restored by judicious administration of hormones and the ovarian imbalance readjusted so that conception may occur. In every sterility case resulting from ovarian dysfunction, a careful analysis of the hormonal status of the patient should be made. This should include a basal metabolism estimation, a study of the basal temperature
STERILITY DUE
Presented at the Eighth Annual Meeting of the American Society for the Study of Sterility, Chicago, Illinois, June 7, 1952. From the Endocrine Clinic, Woman's Hospital, Division of St. Luke's Hospital, New York, New York. I am grateful to Dr. Leon Motyloff, Pathologist at Woman's Hospital, New York, for his help in the classifications of the endometrial biopsies. 327
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[Fertility & Sterility
chart, vaginal smear determinations, pregnandiol assays, and a routine examination of the endometrial biopsies. The administration of hormones without a careful analysis of hormonal status is unwise, for it may not only be harmful but may also place the possibility of pregnancy at a greater distance than if the patient had not been treated at all. The major complaint of patients with ovarian dysfunction is generally that of irregular bleeding or a complete amenorrhea. The irregular bleeding may be associated with oligomenorrhea, menometrorrhagia, or polymenorrhea. The latter may at times reach hemorrhagic proportions. Because of the extreme sensitivity of the endometrium, menstrual irregularities are not uncommon. This does not necessarily indicate that the patient is not ovulating. If, however, there is a hormonal deficiency to the degree of inadequacy or absence of progesterone, sterility is the result. Of all the various tests for ovarian dysfunction the endometrial biopsy is the most important, as it not only indicates the state of the endometrium but produces evidence as to the type of hormonal imbalance which is present. The biopsy may demonstrate a complete atrophy, a proliferative phase, an early or poorly developed secretory phase, a glandular hyperplasia, or many gradations between all of these. It may also show local pathologic conditions resulting from a hormonal imbalance. These may include such changes as edema of the stroma, a delicate and friable stroma, decidual reaction of the stroma, formation of tubular glands, cyst formation, and polyp formation. In a study of endometrial biopsies at the Woman's Hospital, New York, over a number of years, we have been impressed with the large number of ovarian dysfunction cases that show many variations of pathologic changes in the endometrium. These conditions, associated with a hormonal deficiency, may well be a factor in the failure of the patient to conceive. Women who have had ovarian dysfunction and eventually have become pregnant constitute a large proportion of those whose pregnancy is complicated by labor accidents. These include uterine inertia, toxemia of pregnancy, stillborn children, prolonged labors, children with congenital deformities, premature labors, premature separation of the placenta, abortions, and miscarriages. Because of the pathologic conditions and hormonal changes in the endo-
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OVARIAN DYSFUNCTION
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metrium of patients with ovarian dysfunction, we have classified our endometrial biopsies and are thus enabled to place our patients in a definite category based on the endometrial findings. With this classification we are able to treat our patients with greater sureness. The classification is as follows: I. Normal secretory endometrium, normal cyclic ovulation with regular periods. 2. Secretory endometrium with: a. Edema of stroma (with tubular shape of glands). This edema is greater than the amount normally found and is associated with thyroid deficiency. b. Decidual reaction of the stroma (functional hypertrophy). c. Delicate and friable stroma, also often associated with thyroid deficiency. d. Localized glandular hyperplasia. Irregular menstrual periods may accompany this type of endometrium. 3. Proliferative endometrium with: a. Glandular hyperplasia Cyst formation Polyp formation b. Inhibited proliferation Tendency to atrophy 4. Proliferative endometrium without hyperplasia. 5. Atrophy of the endometrium.
If hormonal levels are maintained at normal, ovulation and menstruation remain consistently regular. On the other hand, if these levels become unbalanced from extraneous causes, abnormalities develop with failure of ovulation and a resultant menstrual dysfunction. The fact that menstrual irregularities occur so commonly is partly due to the sensitivity of the endometrium, which is caused by the sudden withdrawals of either estrogen or progesterone. Because of the delicate hormonal balance and the sensitivity of the endometrium to these sudden withdrawals of ovarian hormones, it is not difficult to understand failure to ovulate consistently. The work of Hartman, 3 Comer,! and Novak5 has proved that the anovulatory cycle in the female is not rare. Hamblen 4 estimates this may occur in about 15 per cent of women having regular periods, while Novak6
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puts the figure at a ratio of about 27 per cent. Other workers have given a much higher percentage. The common understanding of an anovulatory cycle is one in which there has been a failure to rupture of the graafian follicle and, therefore, failure of a corpus luteum to form. It is possible that there may be three conditions which cause sterility as a result of ovarian dysfunction. Steinberg7 describes these as follows: ( 1) Anovulation without corpus luteum formation (true anovulatory bleeding); ( 2) Anovulation with subsequent corpus luteum formation ( lutenization of the eggless follicle); ( 3) Ovulation without subsequent corpus luteum formation ( postovulatory early secretory arrest). In the first group there will be a failure of the basal temperature chart to demonstrate a mid-cycle rise and the biopsy will show a proliferative phase or some gradation of it. Corner2 believes this type of anovulatory bleeding to be the result of an estrin deficiency. These patients may have either regular or irregular cycles. It is in this type of patient that a basal temperature is essential over a long period of time to estimate a pattern of possible ovulatory periods occurring at various intervals. The second group is evaluated more on clinical evidence than on a scientific basis. In these cases the basal temperature chart may show failure of a mid-cycle rise and yet the biopsy may demonstrate a typical secretory endometrium. The third group of patients, who in reality are ovulatory, are nevertheless sterile because of an early secretory arrest. Ovulation in these patients may take place, but they will fail to produce a secretory endometrium because of a deficiency or lack of progesterone. These patients may have either short, irregular, or normal cycles. The temperature charts of these patients will exhibit a normal temperature rise at the mid-cycle but the biopsy will fail to exhibit a secretory endometrial phase. I have observed this type of patient with mittleschmerz and pink staining at the time of ovulation, yet the biopsy will present either a poorly developed secretory phase or a proliferative endometrium. A study of 43 patients whose sterility was the result of ovarian dysfunction was undertaken in an effort to estimate the type of hormonal treatment best suited to the individual case. These were selected from the Endocrine Clinic at the Woman's Hospital and from our private practice. The duration of the sterility was from 1 to 14 years. Some cases were treated by thyroid alone, while others were given hor-
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OVARIAN DYSFUNCTION
mones prior to their conception. All patients were studied by means of various hormonal tests prior to their treatment. Endometrial biopsies were repeated as treatment progressed to evaluate endometrial reactions. Of these, 33 women were delivered of normal children, 4 aborted, and 6 are pregnant at the present time. A number have become pregnant a second TABLE 1.
Age Group of Sterility Cases Treated and Types of Menstrual Cycles Number of cases Age group of sterility cases treated (years) 20-25 26-30 31-35 36-41 TOTAL
Age when menstrual periods began (years) 10-13 14-15 16-17 18-19 TOTAL
Menstrual period cycle (days) 21 26 27 28 30 40 60 TOTAL
Menstrual cycles Regular Irregular TOTAL
Menstrual disturbances Amenorrhea Hypomenorrhea Hypermenorrhea Menometrorrhagia Dysmenorrhea
43 7 20 9 7 43 28 13 1 1 43 1 2 1 14 21 1 3 43 15 28 43 6 17 8 11
10
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time. In the second pregnancies, there was 1 ectopic pregnancy and 1 premature separation. In analyzing these subfertile patients we endeavored to differentiate those whose failure to conceive was the result of a lowered basal metabolic rate from those whose sterility was directly due to an ovarian dysfunction. Just what effect thyroid has in aiding conception is not definitely known, but we did note a marked improvement in the endometrium after thyroid was administered and a noticeable regularity in the menstrual cycle. As Rakoff8 has stated, "thyroid extracts have been the sheet anchor in the management of menstrual disorders for a long time." TABLE 2.
Basal metabolism; Endocrine Status; Basal Temperature Charts
Basal metabolism + 5-15 +15-20 +20-25 - 2-10 -10-20 -20-30 Endocrine status Excessive weight gain Chronic cystic mastitis Painful breasts at time of period Hot flushes Spotting (uterine) following period Hirsutism Basal temperature charts Instruction as to ovulation time Ovulation time (days) 12 to 16 17 to 18 18 to 25 26 plus
9
3 1 22 10 3 4
3
14 3
7 1
24 19 31 9 1 2
As indicated by Table 1, the majority of sterility cases were between 26 and 30 years of age. The second highest group was between 30 and 40 years of age. The fact that the older group is nearly as high as the younger group is undoubtedly due to the duration of the sterility and the doubtfulness of their ability to become pregnant. The menstrual cycles of all patients were, for the most part, irregular, and menometrorrhagia was a common complaint.
r
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OVARIAN DYSFUNCTION
In Table 2, it will be noticed that the majority of patients had a lowered basal rate. It is interesting to note the number of times that chronic cystic mastitis occurred, accompanied by painful breasts, at the time of the menstrual period. There were 3 patients who complained of hot flushes, and 7 spotted following their periods. Whenever possible, patients were given basal temperature charts to record their temperature. The others were instructed as to their possible ovulation time as judged from their menstrual cycles. TABLE 3.
~
Types of Uterus and Cervix; Estimated Size of Uteri
Type of uterus and adnexa Normal size Hypoplastic uterus Anteflexed Retroverted Retrocessed Polycystic ovaries Endometriosis Type of cervix Normal Long and pointed Congenital erosion Cervical erosion Cervical myoma Depth of uterus 2-2}~ inches 3 inches plus
29
14 14 10 5 2
1 30 l:j
1 7
3 13
so
The frequency of hypoplastic uteri and acute anteflexion will be noted in Table 3. All of these patients were given estrogen in an effort to develop the uteri. Retroversion and retrocession occurred in a number of cases. The long and pointed cervix almost always accompanied the acutely anteflexed uteri. The majority of the uteri were normal in depth, although 13 cases measured from 2 to 2~~ inches. The treatment of these patients did not follow any set pattern but was based on an analysis of the individual case, that is, on the case history, type of bleeding, basal metabolism, a study of the basal temperature chart and an analysis of the endometrial biopsy. The basal temperature over a number of months showed whether the patients had ovulatory periods interspersed with anovulatory periods, and during observation one or two endometrial biopsies were obtained. If the
FROST
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patient had irregular periods and anovulatory periods, the practice was to place her on cyclic hormonal treatment, with estrogen in the first part of the cycle and progesterone in the latter half. If the cycle was short, the progesterone was started early in the cycle, many times as early as the ninth or tenth day. If we felt we were dealing with a secretory arrest and cycles TABLE 4.
Endometrial Biopsies
TYPE OF STERILITY BASED ON TYPE OF ENDOMETRIAL BIOPSY:
Secretory endometrium with: 1. Edema of stroma 2. Decidual reaction of stroma (functional hypertrophy) 3. Delicate and friable stroma 4. Localized glandular hyperplasia (Polyp formation) (Irregular gland formation)
15 12 9 4
2 5
47
TOTAL
Proliferative endometrium 1. Glandular hyperplasia a. Cyst formation b. Polyp formation 2. Inhibited proliferation (tendency to atrophy) 3. Proliferative endometrium (without hyperplasia) a. Cyst formation b. Edema of stroma c. Tubular glands TOTAL
Atrophy of endometrium Total number of biopsies
16 3
5 9 30 4
7 2 76 4
127
TYPE OF ENDOMETRIAL BIOPSIES FROM PATIENTS WHO ABORTED OR MISCARRIED AFTER TREATMENT
Miscarriage at 4 months Miscarriage at 3 months Ectopic pregnancy Aborted at 2 months Aborted at 2 months
Glandular hyperplasia, proliferative endometrium Delicate and friable stroma Proliferative endometrium, irregular and hypertortuous glands Proliferative endometrium with grandular hyperplasia Proliferative glandular hyperplasia with edema of stroma
were short, progesterone alone in large doses was given. As treatment progressed, biopsies were taken to try to estimate the rate of progress. If the patient had a complete atrophy she was first primed with 1-5 mg. stilbestrol intravaginally until a bleeding was established. She was then given cyclic treatment of estrogen and progesterone.
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No one special type of hormone was used and most hormones were given orally or by the sublingual method. Gonadotrophic hormones were used sparingly. In the last few years progesterone has been given in much larger doses than formerly. Thyroid was administered in each case where the basal rate was below zero, as we believe that a lowered basal rate influences nidation and ovulation unfavorably. Six of our patients became pregnant with thyroid treatment alone. ,
CONCLUSION We have had many failures in our clinic and in our private practice. On the other hand, many cases can be salvaged by the judicious use of hormones and a careful analysis of the endometrial biopsy to estimate the type of sterility. All of our patients were advised as to the administration of vitamins as part of their general treatment and were also given suggestions on hygienic living. Because women who have had ovarian dysfunction and eventually have become pregnant constitute a large number of those whose pregnancy is complicated by accidents, it is essential that a careful study of the endometrial biopsy be made prior to conception. It is also important that hormonal therapy should be instituted to improve the endometrium as much as possible before pregnancy is established. The successful treatment of these infertile patients will depend on the restoration of the normal hormonal levels and the re-establishment of normal ovarian function. Two factors are necessary to accomplish this. The ovaries must be put at rest to allow the overstimulated granulosa and theca elements to regress, and the endometrium must be restored to its normal cyclic phase of proliferation and secretion. These conditions may be brought about either by thyroid alone, estrogen alone, cyclic estrogen and progesterone, or progesterone alone, depending on the individual case under treatment. REFERENCES 1. CoRNER, G. W. Contributions to Embryology 15:73, 1923. 2. CoRNER, G. W. Am. ]. Obst. & Gynec. 38:862, 1939. 3. HARTMAN, C. G. Anat. Rec. 35:13, 1927. 4. HAMBLEN, E. C. Endocrinology of Woman. Springfield, Ill., Charles C Thomas, 1949, p. 329. 5. NovAK, E. ].A.M.A. 94:833, 1930. 6. NovAK, E. Am.]. Obst. & Gynec. 37:605, 1939.
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7. STEINBERG, W. 8.
RAKOFF,
A. E.
[Fertility & Sterility
]. M. Soc. New Jersey 48:326, 1951. M.Clin. North America Nov., 1948, p. 1509.
DISCUSSION DR. LYMA.N W. MASON, Denver, Colo.: I agree with Dr. Frost's opening statement that "sterility due to ovarian dysfunction is one of the most difficult problems the physician is called upon to solve." In fact, I should go further and say that I think in the light of our present knowledge we are usually unable to solve it. By this I mean that the uterine evidences of ovarian dysfunction cannot tell us much as to whether such dysfunction is primary in the ovary or elsewhere, notably in the pituitary. It is only when the primary cause can be diagnosed that intelligent and rational treatment can be instituted. At the present time, I do not think this can often be done. I note that Dr. Frost lists in his report of 43 successful cases those whose period of infertility lasted from 6 months to 2 years. These I would not consider sterile, nor would I do a sterility study on them unless their previous history, such as peritonitis or previous surgery, indicated, or unless they insisted. I consider 2 years without contraceptives and without conception as comprising those in whom a complete study is indicated. I cannot reconcile Dr. Frost's statement that of the 43 cases studied and treated, all of them conceived, with a subsequent statement that "we have had many failures in our clinic and in our private practice." A success of 100 per cent would indeed be phenomenal in the field of sterility. Dr. Frost states that Hamblen estimates the occurrence of anovulatory cyclic bleeding in the female as 15 per cent, while Novak puts the figures at about 27 per cent, with other workers giving a much higher percentage. In women whose uterine bleeding is cyclic, even to a reasonable extent, and not definitely clinically metrorrhagic, these percentages are wholly at variance with my own experience. Only very occasionally do I find that I consider an entire absence of evidence of ovulation in endometria, taken within 4 or 5 hours after the beginning of a period, in women whose bleeding is clinically within normal cyclic limits and of reasonable duration. My own experience is based upon several thousand personal examinations of sections, performed together with Dr. William Black, former Professor of Pathology at the University of Colorado Medical School. While evidences of deficient secretory reaction-indicating a deficient corpus luteum activity-are not infrequent, the entire absence of secretory reaction in the endometria are. The reaction may be splotchy, but almost without exception there are glands whose cells are columnar and vacuolated. I have always considered the finding of a secretory endometrium the best evidence we have that ovulation has occurred, short of observation of the ovary itself or the finding of an ovum. I consider Dr. Frost's use of estrogens and progesterone, as outlined, a purely substitutional type of therapy, whose effects are upon the uterus and not upon the ovary. The uterus is the end organ of the ovary, and it is an axiom that the administration of no endocrine product stimulates its own gland. I think that is the case here. It is my own opinion that the estrogens and progesterone have no
I'
I
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curative action upon the ovary. I have found that ovarian function can be further injured, or the pituitary inhibited, by their prolonged or excessive use. It is of much interest to me that in Dr. Frost's table of treatment, he used thyroid in six out of seven categories in conjunction with estrogens or progesterone, or both. In my opinion, the one fundamental hormone for use in inl:ertility is thyroid given to the limit of the patient's tolerance and continued indefinitely. When we have done this I think we have about used our entire therapeutic armamentarium. Being careful not to use the words "cause of," I find a low basal metabolic rate and the symptoms of hypothyroidism as accompanying findings more frequently in cases of relative infertility than all other abnormal findings put together. I think there is also a place for progesterone in the latter half of the menstmal cycle in those cases in which the endometrial biopsy shows the presence of, but a deficiency in, secretory activity. Lastly, as I have said many times before, what we are most in need of is a therapeutic gonadotropin. I do not believe at the present time that we do have one. I wish to thank Dr. Frost and the Society for the privilege of discussing this provocative and interesting paper.
I,
DR. RoBERT N. RUTHERFORD, Seattle, Wash.: It is indeed a pleasure to have the privilege of discussing Dr. Frost's paper, for he has given a practical working approach to the handling of these distressing problems. We have employed several additional methods for study other than those he has outlined and find of them that we are getting little additional aid. Vaginal smears have been less satisfactory than endometrial biopsy timed for the first hours of flow. This study continues, however. Dr. Frost just touched upon a principle which has been of real value in the occasional case. That involves "putting the ovary to rest" for a few months, thus allowing a leveling of basic ovarian hormone efforts. Not infrequently upon cessation of any of the usual inhibition routines, the ovarian pattern will pick up again spontaneously. Our help from the thyroid has been under study for some time and will be the subject of a further report. We are now midway in a 5-year study which began with the investigation of fatigue states in women, and with them, of problems of depressed or disordered ovarian function. As a general working pattern, the patient is given a basal metabolic test before treatment is begun. This is timed particularly for the early premenstmal phase, for there is some indication that there is a physiologic drop in this determination at that time and an acceleration at ovulation time. We wish to know its lower swing, in other words. If the levels are below -10 at this time, thyroid is started and a repeat determination is done in 1 month. If the patient is tmly hypothyroid thi:m there will be improvement subjectively as well as in the metabolic determination. If the patient feels no better or worse and the metabolic determination shows additional depression, then our feeling is now that this patient is not hypothyroid but hypometabolic. She deserves general medical evaluation to correct any vitiating conditions causing this over-all depression of all body functions. Not infrequently intestinal deficiencies or infestations are found, or other constitutional states
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whose symptoms have not been sufficiently pronounced to have attention brought to them. Other methods of evaluating thyroid function are being followed, namely protein-bound iodine, thyroid uptake, blood cholesterol, and the like. For rough and ready following, the basal metabolic rate has yet to be replaced. If the patient still is unrelieved, we have used low-dosage irradiation with fair success; but have not used it after the age of 35 for fear of permanent depression of ovarian function. The literature on this is abundant and good. Our final effort comes after 2 years of treatment by any of the above methods (and often all), and is surgical. We have been impressed with the problem of difficulty in follicle rupture in these patients. In the younger group, we often will find the ovarian tunica so heavy that it mechanically interferes with rupture of the follicle. The problem of the Stein-Leventhal syndrome is known to all of us. We now tend to regard this as evidence of ovarian hypogenitalism, much as the other internal genitalia manifest immaturity of function because of their congenital problem. Another group will demonstrate a thickened tunica as a result of pelvic inflammation or postoperative scarring. A final group would suggest that after the age of 35 there is a progressive aging of the capsule with degenerative changes within the blood vessels which may affect ovarian function. Weed has indicated this in his report. In any event, these patients are refractory to hormone stimulation, often to irradiation, and have shown an increase in good results if one does the classical wedge resection. Again, we are all aware of the hypothetical justification for this procedure. May I again congratulate Dr. Frost upon his excellent presentation and Dr. Mason for his emphasizing certain aspects of the value of thyroid. It has been a privilege to discuss this study. DR. ABNER I. WEISMAN, New York, N.Y.: Your classification of mild and severe sterility confuses me.
III
DR. INGLIS F. FROST, Morristown, N. ]. (closing): There is no sharp line of division between the so-called "mild" sterility cases and the more severe type of sterility due to ovarian dysfunction. The differentiation is based on the history, the type of menstruation, the duration of the sterility, and the findings of the endometrial biopsy. The milder types of sterility may have irregular menstrual periods, anovulatory in character. These may be the result of a lowered thyroid activity or a primary ovarian dysfunction. The endometrial biopsy in these cases will often exhibit a proliferative or a secretory phase with localized areas of glandular hyperplasia. The more severe types of sterility due to ovarian dysfunction may also have irregular menstrual periods or may have a complete amenorrhea. If these cases have menstrual periods, they are frequently profuse in character, often producing hemorrhage. These cases may be the result of a primary ovarian dysfunction but are more often the result of ovarian dysfunction secondary to pituitary dysfunction. The endometrial biopsy may again vary from an atrophic endometrium to a proliferation phase or a complete glandular hyperplasia. The difference between the mild and severe types of sterility is purely an arbitrary distinction and should be based, I should judge, on whether we are dealing with a primary ovarian dysfunction or an ovarian dysfunction secondary to a pituitary dysfunction.
Inglis F. Frost, M.D.
to ovarian dysfunction is one of the most difficult sterility problems the physician is called upon to treat. It constitutes about one-fifth of all the conditions which contribute to the infertility of the married couple. There are many factors which may cause sterility aside from ovarian dysfunction and any one of these, or more than one, may accompany the nonfunctioning ovary. These must be eliminated before deciding that the sterility is due only to a hormonal deficiency. Many endocrinologists feel that the treatment of sterility due to ovarian dysfunction is without merit. This is undoubtedly true of certain cases in which the dysfunction is so fundamental that any type of hormonal treatment to re-establish ovulation would be a useless procedure. There are many cases, however, in which the ovarian deficiency can be restored by judicious administration of hormones and the ovarian imbalance readjusted so that conception may occur. In every sterility case resulting from ovarian dysfunction, a careful analysis of the hormonal status of the patient should be made. This should include a basal metabolism estimation, a study of the basal temperature
STERILITY DUE
Presented at the Eighth Annual Meeting of the American Society for the Study of Sterility, Chicago, Illinois, June 7, 1952. From the Endocrine Clinic, Woman's Hospital, Division of St. Luke's Hospital, New York, New York. I am grateful to Dr. Leon Motyloff, Pathologist at Woman's Hospital, New York, for his help in the classifications of the endometrial biopsies. 327
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[Fertility & Sterility
chart, vaginal smear determinations, pregnandiol assays, and a routine examination of the endometrial biopsies. The administration of hormones without a careful analysis of hormonal status is unwise, for it may not only be harmful but may also place the possibility of pregnancy at a greater distance than if the patient had not been treated at all. The major complaint of patients with ovarian dysfunction is generally that of irregular bleeding or a complete amenorrhea. The irregular bleeding may be associated with oligomenorrhea, menometrorrhagia, or polymenorrhea. The latter may at times reach hemorrhagic proportions. Because of the extreme sensitivity of the endometrium, menstrual irregularities are not uncommon. This does not necessarily indicate that the patient is not ovulating. If, however, there is a hormonal deficiency to the degree of inadequacy or absence of progesterone, sterility is the result. Of all the various tests for ovarian dysfunction the endometrial biopsy is the most important, as it not only indicates the state of the endometrium but produces evidence as to the type of hormonal imbalance which is present. The biopsy may demonstrate a complete atrophy, a proliferative phase, an early or poorly developed secretory phase, a glandular hyperplasia, or many gradations between all of these. It may also show local pathologic conditions resulting from a hormonal imbalance. These may include such changes as edema of the stroma, a delicate and friable stroma, decidual reaction of the stroma, formation of tubular glands, cyst formation, and polyp formation. In a study of endometrial biopsies at the Woman's Hospital, New York, over a number of years, we have been impressed with the large number of ovarian dysfunction cases that show many variations of pathologic changes in the endometrium. These conditions, associated with a hormonal deficiency, may well be a factor in the failure of the patient to conceive. Women who have had ovarian dysfunction and eventually have become pregnant constitute a large proportion of those whose pregnancy is complicated by labor accidents. These include uterine inertia, toxemia of pregnancy, stillborn children, prolonged labors, children with congenital deformities, premature labors, premature separation of the placenta, abortions, and miscarriages. Because of the pathologic conditions and hormonal changes in the endo-
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metrium of patients with ovarian dysfunction, we have classified our endometrial biopsies and are thus enabled to place our patients in a definite category based on the endometrial findings. With this classification we are able to treat our patients with greater sureness. The classification is as follows: I. Normal secretory endometrium, normal cyclic ovulation with regular periods. 2. Secretory endometrium with: a. Edema of stroma (with tubular shape of glands). This edema is greater than the amount normally found and is associated with thyroid deficiency. b. Decidual reaction of the stroma (functional hypertrophy). c. Delicate and friable stroma, also often associated with thyroid deficiency. d. Localized glandular hyperplasia. Irregular menstrual periods may accompany this type of endometrium. 3. Proliferative endometrium with: a. Glandular hyperplasia Cyst formation Polyp formation b. Inhibited proliferation Tendency to atrophy 4. Proliferative endometrium without hyperplasia. 5. Atrophy of the endometrium.
If hormonal levels are maintained at normal, ovulation and menstruation remain consistently regular. On the other hand, if these levels become unbalanced from extraneous causes, abnormalities develop with failure of ovulation and a resultant menstrual dysfunction. The fact that menstrual irregularities occur so commonly is partly due to the sensitivity of the endometrium, which is caused by the sudden withdrawals of either estrogen or progesterone. Because of the delicate hormonal balance and the sensitivity of the endometrium to these sudden withdrawals of ovarian hormones, it is not difficult to understand failure to ovulate consistently. The work of Hartman, 3 Comer,! and Novak5 has proved that the anovulatory cycle in the female is not rare. Hamblen 4 estimates this may occur in about 15 per cent of women having regular periods, while Novak6
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puts the figure at a ratio of about 27 per cent. Other workers have given a much higher percentage. The common understanding of an anovulatory cycle is one in which there has been a failure to rupture of the graafian follicle and, therefore, failure of a corpus luteum to form. It is possible that there may be three conditions which cause sterility as a result of ovarian dysfunction. Steinberg7 describes these as follows: ( 1) Anovulation without corpus luteum formation (true anovulatory bleeding); ( 2) Anovulation with subsequent corpus luteum formation ( lutenization of the eggless follicle); ( 3) Ovulation without subsequent corpus luteum formation ( postovulatory early secretory arrest). In the first group there will be a failure of the basal temperature chart to demonstrate a mid-cycle rise and the biopsy will show a proliferative phase or some gradation of it. Corner2 believes this type of anovulatory bleeding to be the result of an estrin deficiency. These patients may have either regular or irregular cycles. It is in this type of patient that a basal temperature is essential over a long period of time to estimate a pattern of possible ovulatory periods occurring at various intervals. The second group is evaluated more on clinical evidence than on a scientific basis. In these cases the basal temperature chart may show failure of a mid-cycle rise and yet the biopsy may demonstrate a typical secretory endometrium. The third group of patients, who in reality are ovulatory, are nevertheless sterile because of an early secretory arrest. Ovulation in these patients may take place, but they will fail to produce a secretory endometrium because of a deficiency or lack of progesterone. These patients may have either short, irregular, or normal cycles. The temperature charts of these patients will exhibit a normal temperature rise at the mid-cycle but the biopsy will fail to exhibit a secretory endometrial phase. I have observed this type of patient with mittleschmerz and pink staining at the time of ovulation, yet the biopsy will present either a poorly developed secretory phase or a proliferative endometrium. A study of 43 patients whose sterility was the result of ovarian dysfunction was undertaken in an effort to estimate the type of hormonal treatment best suited to the individual case. These were selected from the Endocrine Clinic at the Woman's Hospital and from our private practice. The duration of the sterility was from 1 to 14 years. Some cases were treated by thyroid alone, while others were given hor-
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OVARIAN DYSFUNCTION
mones prior to their conception. All patients were studied by means of various hormonal tests prior to their treatment. Endometrial biopsies were repeated as treatment progressed to evaluate endometrial reactions. Of these, 33 women were delivered of normal children, 4 aborted, and 6 are pregnant at the present time. A number have become pregnant a second TABLE 1.
Age Group of Sterility Cases Treated and Types of Menstrual Cycles Number of cases Age group of sterility cases treated (years) 20-25 26-30 31-35 36-41 TOTAL
Age when menstrual periods began (years) 10-13 14-15 16-17 18-19 TOTAL
Menstrual period cycle (days) 21 26 27 28 30 40 60 TOTAL
Menstrual cycles Regular Irregular TOTAL
Menstrual disturbances Amenorrhea Hypomenorrhea Hypermenorrhea Menometrorrhagia Dysmenorrhea
43 7 20 9 7 43 28 13 1 1 43 1 2 1 14 21 1 3 43 15 28 43 6 17 8 11
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time. In the second pregnancies, there was 1 ectopic pregnancy and 1 premature separation. In analyzing these subfertile patients we endeavored to differentiate those whose failure to conceive was the result of a lowered basal metabolic rate from those whose sterility was directly due to an ovarian dysfunction. Just what effect thyroid has in aiding conception is not definitely known, but we did note a marked improvement in the endometrium after thyroid was administered and a noticeable regularity in the menstrual cycle. As Rakoff8 has stated, "thyroid extracts have been the sheet anchor in the management of menstrual disorders for a long time." TABLE 2.
Basal metabolism; Endocrine Status; Basal Temperature Charts
Basal metabolism + 5-15 +15-20 +20-25 - 2-10 -10-20 -20-30 Endocrine status Excessive weight gain Chronic cystic mastitis Painful breasts at time of period Hot flushes Spotting (uterine) following period Hirsutism Basal temperature charts Instruction as to ovulation time Ovulation time (days) 12 to 16 17 to 18 18 to 25 26 plus
9
3 1 22 10 3 4
3
14 3
7 1
24 19 31 9 1 2
As indicated by Table 1, the majority of sterility cases were between 26 and 30 years of age. The second highest group was between 30 and 40 years of age. The fact that the older group is nearly as high as the younger group is undoubtedly due to the duration of the sterility and the doubtfulness of their ability to become pregnant. The menstrual cycles of all patients were, for the most part, irregular, and menometrorrhagia was a common complaint.
r
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OVARIAN DYSFUNCTION
In Table 2, it will be noticed that the majority of patients had a lowered basal rate. It is interesting to note the number of times that chronic cystic mastitis occurred, accompanied by painful breasts, at the time of the menstrual period. There were 3 patients who complained of hot flushes, and 7 spotted following their periods. Whenever possible, patients were given basal temperature charts to record their temperature. The others were instructed as to their possible ovulation time as judged from their menstrual cycles. TABLE 3.
~
Types of Uterus and Cervix; Estimated Size of Uteri
Type of uterus and adnexa Normal size Hypoplastic uterus Anteflexed Retroverted Retrocessed Polycystic ovaries Endometriosis Type of cervix Normal Long and pointed Congenital erosion Cervical erosion Cervical myoma Depth of uterus 2-2}~ inches 3 inches plus
29
14 14 10 5 2
1 30 l:j
1 7
3 13
so
The frequency of hypoplastic uteri and acute anteflexion will be noted in Table 3. All of these patients were given estrogen in an effort to develop the uteri. Retroversion and retrocession occurred in a number of cases. The long and pointed cervix almost always accompanied the acutely anteflexed uteri. The majority of the uteri were normal in depth, although 13 cases measured from 2 to 2~~ inches. The treatment of these patients did not follow any set pattern but was based on an analysis of the individual case, that is, on the case history, type of bleeding, basal metabolism, a study of the basal temperature chart and an analysis of the endometrial biopsy. The basal temperature over a number of months showed whether the patients had ovulatory periods interspersed with anovulatory periods, and during observation one or two endometrial biopsies were obtained. If the
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patient had irregular periods and anovulatory periods, the practice was to place her on cyclic hormonal treatment, with estrogen in the first part of the cycle and progesterone in the latter half. If the cycle was short, the progesterone was started early in the cycle, many times as early as the ninth or tenth day. If we felt we were dealing with a secretory arrest and cycles TABLE 4.
Endometrial Biopsies
TYPE OF STERILITY BASED ON TYPE OF ENDOMETRIAL BIOPSY:
Secretory endometrium with: 1. Edema of stroma 2. Decidual reaction of stroma (functional hypertrophy) 3. Delicate and friable stroma 4. Localized glandular hyperplasia (Polyp formation) (Irregular gland formation)
15 12 9 4
2 5
47
TOTAL
Proliferative endometrium 1. Glandular hyperplasia a. Cyst formation b. Polyp formation 2. Inhibited proliferation (tendency to atrophy) 3. Proliferative endometrium (without hyperplasia) a. Cyst formation b. Edema of stroma c. Tubular glands TOTAL
Atrophy of endometrium Total number of biopsies
16 3
5 9 30 4
7 2 76 4
127
TYPE OF ENDOMETRIAL BIOPSIES FROM PATIENTS WHO ABORTED OR MISCARRIED AFTER TREATMENT
Miscarriage at 4 months Miscarriage at 3 months Ectopic pregnancy Aborted at 2 months Aborted at 2 months
Glandular hyperplasia, proliferative endometrium Delicate and friable stroma Proliferative endometrium, irregular and hypertortuous glands Proliferative endometrium with grandular hyperplasia Proliferative glandular hyperplasia with edema of stroma
were short, progesterone alone in large doses was given. As treatment progressed, biopsies were taken to try to estimate the rate of progress. If the patient had a complete atrophy she was first primed with 1-5 mg. stilbestrol intravaginally until a bleeding was established. She was then given cyclic treatment of estrogen and progesterone.
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No one special type of hormone was used and most hormones were given orally or by the sublingual method. Gonadotrophic hormones were used sparingly. In the last few years progesterone has been given in much larger doses than formerly. Thyroid was administered in each case where the basal rate was below zero, as we believe that a lowered basal rate influences nidation and ovulation unfavorably. Six of our patients became pregnant with thyroid treatment alone. ,
CONCLUSION We have had many failures in our clinic and in our private practice. On the other hand, many cases can be salvaged by the judicious use of hormones and a careful analysis of the endometrial biopsy to estimate the type of sterility. All of our patients were advised as to the administration of vitamins as part of their general treatment and were also given suggestions on hygienic living. Because women who have had ovarian dysfunction and eventually have become pregnant constitute a large number of those whose pregnancy is complicated by accidents, it is essential that a careful study of the endometrial biopsy be made prior to conception. It is also important that hormonal therapy should be instituted to improve the endometrium as much as possible before pregnancy is established. The successful treatment of these infertile patients will depend on the restoration of the normal hormonal levels and the re-establishment of normal ovarian function. Two factors are necessary to accomplish this. The ovaries must be put at rest to allow the overstimulated granulosa and theca elements to regress, and the endometrium must be restored to its normal cyclic phase of proliferation and secretion. These conditions may be brought about either by thyroid alone, estrogen alone, cyclic estrogen and progesterone, or progesterone alone, depending on the individual case under treatment. REFERENCES 1. CoRNER, G. W. Contributions to Embryology 15:73, 1923. 2. CoRNER, G. W. Am. ]. Obst. & Gynec. 38:862, 1939. 3. HARTMAN, C. G. Anat. Rec. 35:13, 1927. 4. HAMBLEN, E. C. Endocrinology of Woman. Springfield, Ill., Charles C Thomas, 1949, p. 329. 5. NovAK, E. ].A.M.A. 94:833, 1930. 6. NovAK, E. Am.]. Obst. & Gynec. 37:605, 1939.
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7. STEINBERG, W. 8.
RAKOFF,
A. E.
[Fertility & Sterility
]. M. Soc. New Jersey 48:326, 1951. M.Clin. North America Nov., 1948, p. 1509.
DISCUSSION DR. LYMA.N W. MASON, Denver, Colo.: I agree with Dr. Frost's opening statement that "sterility due to ovarian dysfunction is one of the most difficult problems the physician is called upon to solve." In fact, I should go further and say that I think in the light of our present knowledge we are usually unable to solve it. By this I mean that the uterine evidences of ovarian dysfunction cannot tell us much as to whether such dysfunction is primary in the ovary or elsewhere, notably in the pituitary. It is only when the primary cause can be diagnosed that intelligent and rational treatment can be instituted. At the present time, I do not think this can often be done. I note that Dr. Frost lists in his report of 43 successful cases those whose period of infertility lasted from 6 months to 2 years. These I would not consider sterile, nor would I do a sterility study on them unless their previous history, such as peritonitis or previous surgery, indicated, or unless they insisted. I consider 2 years without contraceptives and without conception as comprising those in whom a complete study is indicated. I cannot reconcile Dr. Frost's statement that of the 43 cases studied and treated, all of them conceived, with a subsequent statement that "we have had many failures in our clinic and in our private practice." A success of 100 per cent would indeed be phenomenal in the field of sterility. Dr. Frost states that Hamblen estimates the occurrence of anovulatory cyclic bleeding in the female as 15 per cent, while Novak puts the figures at about 27 per cent, with other workers giving a much higher percentage. In women whose uterine bleeding is cyclic, even to a reasonable extent, and not definitely clinically metrorrhagic, these percentages are wholly at variance with my own experience. Only very occasionally do I find that I consider an entire absence of evidence of ovulation in endometria, taken within 4 or 5 hours after the beginning of a period, in women whose bleeding is clinically within normal cyclic limits and of reasonable duration. My own experience is based upon several thousand personal examinations of sections, performed together with Dr. William Black, former Professor of Pathology at the University of Colorado Medical School. While evidences of deficient secretory reaction-indicating a deficient corpus luteum activity-are not infrequent, the entire absence of secretory reaction in the endometria are. The reaction may be splotchy, but almost without exception there are glands whose cells are columnar and vacuolated. I have always considered the finding of a secretory endometrium the best evidence we have that ovulation has occurred, short of observation of the ovary itself or the finding of an ovum. I consider Dr. Frost's use of estrogens and progesterone, as outlined, a purely substitutional type of therapy, whose effects are upon the uterus and not upon the ovary. The uterus is the end organ of the ovary, and it is an axiom that the administration of no endocrine product stimulates its own gland. I think that is the case here. It is my own opinion that the estrogens and progesterone have no
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curative action upon the ovary. I have found that ovarian function can be further injured, or the pituitary inhibited, by their prolonged or excessive use. It is of much interest to me that in Dr. Frost's table of treatment, he used thyroid in six out of seven categories in conjunction with estrogens or progesterone, or both. In my opinion, the one fundamental hormone for use in inl:ertility is thyroid given to the limit of the patient's tolerance and continued indefinitely. When we have done this I think we have about used our entire therapeutic armamentarium. Being careful not to use the words "cause of," I find a low basal metabolic rate and the symptoms of hypothyroidism as accompanying findings more frequently in cases of relative infertility than all other abnormal findings put together. I think there is also a place for progesterone in the latter half of the menstmal cycle in those cases in which the endometrial biopsy shows the presence of, but a deficiency in, secretory activity. Lastly, as I have said many times before, what we are most in need of is a therapeutic gonadotropin. I do not believe at the present time that we do have one. I wish to thank Dr. Frost and the Society for the privilege of discussing this provocative and interesting paper.
I,
DR. RoBERT N. RUTHERFORD, Seattle, Wash.: It is indeed a pleasure to have the privilege of discussing Dr. Frost's paper, for he has given a practical working approach to the handling of these distressing problems. We have employed several additional methods for study other than those he has outlined and find of them that we are getting little additional aid. Vaginal smears have been less satisfactory than endometrial biopsy timed for the first hours of flow. This study continues, however. Dr. Frost just touched upon a principle which has been of real value in the occasional case. That involves "putting the ovary to rest" for a few months, thus allowing a leveling of basic ovarian hormone efforts. Not infrequently upon cessation of any of the usual inhibition routines, the ovarian pattern will pick up again spontaneously. Our help from the thyroid has been under study for some time and will be the subject of a further report. We are now midway in a 5-year study which began with the investigation of fatigue states in women, and with them, of problems of depressed or disordered ovarian function. As a general working pattern, the patient is given a basal metabolic test before treatment is begun. This is timed particularly for the early premenstmal phase, for there is some indication that there is a physiologic drop in this determination at that time and an acceleration at ovulation time. We wish to know its lower swing, in other words. If the levels are below -10 at this time, thyroid is started and a repeat determination is done in 1 month. If the patient is tmly hypothyroid thi:m there will be improvement subjectively as well as in the metabolic determination. If the patient feels no better or worse and the metabolic determination shows additional depression, then our feeling is now that this patient is not hypothyroid but hypometabolic. She deserves general medical evaluation to correct any vitiating conditions causing this over-all depression of all body functions. Not infrequently intestinal deficiencies or infestations are found, or other constitutional states
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whose symptoms have not been sufficiently pronounced to have attention brought to them. Other methods of evaluating thyroid function are being followed, namely protein-bound iodine, thyroid uptake, blood cholesterol, and the like. For rough and ready following, the basal metabolic rate has yet to be replaced. If the patient still is unrelieved, we have used low-dosage irradiation with fair success; but have not used it after the age of 35 for fear of permanent depression of ovarian function. The literature on this is abundant and good. Our final effort comes after 2 years of treatment by any of the above methods (and often all), and is surgical. We have been impressed with the problem of difficulty in follicle rupture in these patients. In the younger group, we often will find the ovarian tunica so heavy that it mechanically interferes with rupture of the follicle. The problem of the Stein-Leventhal syndrome is known to all of us. We now tend to regard this as evidence of ovarian hypogenitalism, much as the other internal genitalia manifest immaturity of function because of their congenital problem. Another group will demonstrate a thickened tunica as a result of pelvic inflammation or postoperative scarring. A final group would suggest that after the age of 35 there is a progressive aging of the capsule with degenerative changes within the blood vessels which may affect ovarian function. Weed has indicated this in his report. In any event, these patients are refractory to hormone stimulation, often to irradiation, and have shown an increase in good results if one does the classical wedge resection. Again, we are all aware of the hypothetical justification for this procedure. May I again congratulate Dr. Frost upon his excellent presentation and Dr. Mason for his emphasizing certain aspects of the value of thyroid. It has been a privilege to discuss this study. DR. ABNER I. WEISMAN, New York, N.Y.: Your classification of mild and severe sterility confuses me.
III
DR. INGLIS F. FROST, Morristown, N. ]. (closing): There is no sharp line of division between the so-called "mild" sterility cases and the more severe type of sterility due to ovarian dysfunction. The differentiation is based on the history, the type of menstruation, the duration of the sterility, and the findings of the endometrial biopsy. The milder types of sterility may have irregular menstrual periods, anovulatory in character. These may be the result of a lowered thyroid activity or a primary ovarian dysfunction. The endometrial biopsy in these cases will often exhibit a proliferative or a secretory phase with localized areas of glandular hyperplasia. The more severe types of sterility due to ovarian dysfunction may also have irregular menstrual periods or may have a complete amenorrhea. If these cases have menstrual periods, they are frequently profuse in character, often producing hemorrhage. These cases may be the result of a primary ovarian dysfunction but are more often the result of ovarian dysfunction secondary to pituitary dysfunction. The endometrial biopsy may again vary from an atrophic endometrium to a proliferation phase or a complete glandular hyperplasia. The difference between the mild and severe types of sterility is purely an arbitrary distinction and should be based, I should judge, on whether we are dealing with a primary ovarian dysfunction or an ovarian dysfunction secondary to a pituitary dysfunction.